A CRISPR dropout screen identifies genetic vulnerabilities in acute myeloid leukaemia. Kosuke Yusa Wellcome Trust Sanger Institute
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1 A CRISPR dropout screen identifies genetic vulnerabilities in acute myeloid leukaemia Kosuke Yusa Wellcome Trust Sanger Institute
2 CRISPR screens Dec 2013 PLX4720 resistance in BRAF V600E melanoma. Resistance to etoposide in leukaemic cells. Resistance to a toxin in mouse ES cells. How about dropout? Genes essential for cell identity Genes required for tumour cell proliferation Genes whose mutation sensitises to drugs Novel therapeutic targets
3 End point CRISPR screening in drug target discovery Genetic vulnerability screen Pooled lentiviral library Cytotoxic/cytostatic Cas9-expressing cells Increased proliferation Initial population Drug resistance/sensitization screen Pooled lentiviral library Non-treated Cas9-expressing cells Sensitive Treated Resistant
4 Dropout with the v1 Mouse library Dropout in mouse ESCs with v1 library (analysed using MAGeCK, Li et al. 2014) Ribosomal genes Sox2 Pou5f1 Nanog
5 Dropout with the v1 Mouse library Dropout in mouse ESCs with v1 library (analysed using MAGeCK, Li et al. 2014) Ribosomal genes Sox2 Pou5f1 Nanog Particular bases favoured T at the 3 end disfavoured due to poliii termination
6 Higher KO efficiency with the improved grna scaffold
7 V2 library generation Dropout in mouse ESCs with v1 library (analysed using MAGeCK, Li et al. 2014) Ribosomal genes Sox2 Pou5f1 Particular bases favoured Nanog v2 GW-gRNA design pipeline - Avoid T stretch at the 3 end - Not use on-target prediction - Design 5 guides per gene by relaxing cut-off T at the 3 end disfavoured due to poliii termination Backbone vector - Use the improved scaffold
8 Improved gene depletion with the v2 library Dropout in mouse ESCs with v1 library Dropout in mouse ESCs with v2 library Ribosomal genes Sox2 Pou5f1 Pou5f1 Sox2 Ribosomal genes Nanog Nanog
9 Improved library does not impair specificity grna-level scatter plot Gene-level scatter plot
10 BFP-positive [%] BFP CRISPR screening toolkit No virus 1 ul/well 2 ul/well 5 ul/well 10 ul/well 20 ul/well Virus [ul/well]
11 CRISPR screening toolkit Cas9 functional assay Mock Empty ggfp Wt mescs Cas9 mescs
12 Counts More even representation with Twist s oligo pool v # reads per guide Unpublished
13 Counts Counts Counts More even representation with Twist s oligo pool v1 v # reads per guide Human v Human v1.1-twist 95.23% log2 (normalised readcounts) 95.19% log2 (normalised readcounts) Unpublished
14 CRISPR screen in HT-29 colon cancer cell line Human v1 HT-29 colon cancer HT-29C clone 3 x3 7~25 dpi Number of depleted genes
15 CRISPR screen in HT-29 colon cancer cell line Human v1 HT-29 colon cancer HT-29C clone 3 x3 7~25 dpi Biased region
16 CRISPR screen in HT-29 colon cancer cell line Human v1 HT-29 colon cancer HT-29C clone 3 x3 7~25 dpi Chr 8 Chr 20
17 CRISPR screen in HT-29 colon cancer cell line Human v1 HT-29 colon cancer HT-29C clone 3 x3 7~25 dpi Gene depletion in time-course analyses Translation Splicing Cell cycle Mitochondria
18 CRISPR screen in 5 AML cell lines Cell lines MOLM-13 Collaboration with George Vassiliou, Kostas Tzelepis MV4-11 HL-60 OCI-AML2 OCI-AML3 HT-29 Nature Methods 2013 HT-1080 AMLs 492 HT-1080 HT-29
19 Genetic and pharmacological validation of KAT2A Validation by grna KAT2A inhibitor, MB-3
20 KAT2A suppression induces differentiation and apoptosis RNA-seq (MOLM-13, 48h MB-3) ChIP-qPCR (MOLM-13, 24h MB-3)
21 KAT2A inhibition induces differentiation and apoptosis Differentiation Apoptosis
22 KAT2A inhibition is effective against human primary AML cells AML samples CD34+ cells
23 Summary Optimised CRISPR-Cas9 platform for genome-wide screens Genome-wide recessive screen focused on AML Identified a large number of potential therapeutic targets Identified KAT2A as a promising anti-aml target
24 Acknowledgements Wellcome Trust Sanger Institute Team 203 Hiroko Koike-Yusa Swee Hoe Ong Leandro Lo Cascio Meng Li Bahar Mirshekar-Syahkal Sianadh Dunn Jason Yu Yan Zi Au Shuhei Ohnishi Team 154 Yilong Li Team 163 Kostas Tzelepis Etienne De Braekeleer George Vassiliou Team 215 Fiona Behan Mathew Garnett Team 30 Sumana Sharma Shan Chong Gavin Wrights EMBL-EBI Francesco Iorio Julio Saez-Rodriguez University of Cambridge Brian Huntly Cristina Pina Funding Team 155 Vera Grinkevich Steven Williams Ultan McDermott Sequence facility Flow cytometry facility RSF
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